Corticotropin-Releasing Factor (hereinafter abbreviated as “CRF”) is a neuropeptide consisting of 41 amino acids which was first isolated from ovine hypothalamus [Science, 213, 1394 (1981)], after which its presence was also confirmed in rats [Proc. Natl. Acad. Sci. USA, 80, 4851 (1983)] and in humans [EMBO J. 5, 775 (1983)]. CRF is most abundant in the pituitary gland and hypothalamus, and is also widely distributed throughout the cerebral cortex, cerebellum and other area of the brain. Its presence has also been confirmed in peripheral tissue such as the placenta, adrenal gland, lung, liver, pancreas and digestive tract [J. Clin. Endocrinol. Metab., 67, 768 (1988), Regul. Pept. 18, 173 (1988), Peptides, 5 (Suppl. 1), 71 (1984)]. Two subtype CRF receptor has been described, CRF1 and CRF2, and the CRF1 receptor is reported to be widely distributed in the cerebral cortex, cerebellum, olfactory bulb, pituitary gland, amygdaloid nucleus and elsewhere. Recently, 2 subtypes of the CRF2 receptor have been confirmed, CRF2α and CRF2β, of which it has been discovered that CRF2α receptors are abundantly distributed in the hypothalamus, septal nucleus and choroids plexus, while CRF2β receptors are primarily distributed in peripheral tissue such as the skeletal muscle, or in the cerebral blood vessels of the central nervous system [J. Neuroscience, 15(10)6340 (1995); Endocrinology, 137, 72, (1996); BBA, 1352, 129 (1997)]. The fact that each of these receptors has a different distribution profile suggests that their roles are also different. CRF is produced and secreted in the hypothalamus and promotes stress-induced release of adrenocorticotropic hormone (ACTH) [Recent Prog. Horm. Res., 39, 245 (1983)]. In addition to its endocrine role, CRF also functions as a neurotransmitter or neuromodulator in the brain, integrating electrophysiological, autonomic and behavioral changes in response to stress [Brain Res. Rev., 15, 71 (1990); Pharmacol. Rev., 43, 425 (1991)].
CRF has been implicated in a variety of disease to date, as indicated by the following publications.
It was reported that elevated concentrations of CRF in the cerebrospinal fluid of patients with major depression compared with healthy controls [Am. J. Psychiatry, 144(7), 873 (1987)]; CRF-mRNA levels in the hypothalamus of depressive patients are higher than that of healthy individuals [Am. J. Psychiatry, 152, 1372 (1995)]; CRF receptors in cerebral cortex are reduced in suicide victims [Arch. Gen. Psychiatry, 45, 577 (1988)]; plasma ACTH increase is diminished with administration of CRF to depressive patients [N. Engl. J. Med., 314, 1329 (1986)]; CRF levels in the cerebrospinal fluid of some anxiety patients with obsessive-compulsive disorder, posttraumatic stress disorder or Tourette's syndrome are higher than in that of healthy individuals [Arch. Gen. Psychiatry, 51, 794 (1994); Am. J. Psychiatry, 154, 624 (1997); Biol. Psychiatry, 39, 776 (1996)]; plasma ACTH increase is diminished with administration of CRF to panic disorder patients [Am. J. Psychiatry, 143, 896 (1986)]; anxiety behavior has been observed in experimental animals by central administration of CRF [Brain Res., 574, 70 (1992); J. Neurosci., 10(1), 176 (1992)]. In addition, anxiety behavior is observed more frequently in CRF overexpressing mice than in normal mice [J. Neurosci., 14(5), 2579 (1994)], and CRF levels in the locus coeruleus are reduced by administration of anxiolytics [J. Pharmaco. Exp. Ther., 258, 349 (1991)]. Also, the peptide CRF antagonist α-helical CRF (9-41) exhibits an anxiolytic effect in animal models [Brain Res., 509, 80 (1990); Regulatory Peptides, 18, 37 (1987); J. Neurosci., 14(5), 2579 (1994)]; abnormal behavior withdrawal from alcohol or addictive drugs such as cocaine are inhibited by the peptide CRF antagonist α-helical CRF (9-41) [Psychopharmacology, 103, 227 (1991)]; CRF inhibits sexual behavior in rats [Nature, 305, 232 (1983)]; CRF reduces sleep in rats and is thus implicated the involvement in sleep disorder [Pharmacol. Biochem. Behav., 26, 699 (1987)]; the peptide CRF antagonist α-helical CRF (9-41) suppresses brain damage or electroencephalogram disturbances due to brain ischemia or NMDA receptor activation [Brain Res., 545, 339 (1991), Brain Res., 656, 405 (1994)]; CRF elicits electroencephalogram and induces convulsions [Brain Res., 278, 332 (1983)]; cerebrospinal CRF levels are elevated in schizophrenic patients compared with healthy individuals [Am. J. Psychiatry, 144(7), 873 (1987)]; CRF contents in cerebral cortex is reduced in Alzheimer's patients, Parkinson's patients and progressive supranuclear palsy patients [Neurology, 37, 905 (1987)]; and CRF is reduced in the ganglia in Huntington's disease [Brain Res., 437, 355 (1987), Neurology, 37, 905 (1987)]. In addition, CRF administration has been found to enhance learning and memory in rats [Nature, 378, 284 (1995); Neuroendocrinology, 57, 1071 (1993)], and CRF levels of cerebrospinal fluid are reduced in amyotrophic lateral sclerosis patients. Oversecretion of ACTH and adrenocorticosteroids are exhibited in CRF overexpressing mice, these mice display abnormalities similar to Cushing's syndrome, including muscular atrophy, alopecia and infertility [Endocrinology, 130(6), 3378 (1992)]; cerebrospinal CRF levels are elevated in anorexia nervosa patients compared with healthy individuals, and plasma ACTH increase is low with administration of CRF to anorexia nervosa patients [J. Clin. Endocrinol. Metab., 62, 319 (1986)]; and CRF suppress food consumption in experimental animals [Neuropharmacology, 22 (3A), 337 (1983)]. Moreover, the peptide CRF antagonist α-helical CRF (9-41) reverses stress-induced reduction in food intake in animal models [Brain Res. Bull., 17(3), 285 (1986)]; CRF has suppressed body weight gain in genetically obese animals [Physiol. Behav., 45, 565 (1989)]; a link has been suggested between low CRF levels and obesity syndrome [Endocrinology, 130, 1931 (1992)]; the anorexic action and body weight-reducing effects of serotonin reuptake inhibitors has been possibly linked to CRF release [Pharmacol. Rev., 43, 425 (1991)]; and CRF acts centrally or peripherally to inhibit gastric contraction and reduce gastric emptying [Regulatory Peptides, 21, 173 (1988); Am. J. Physiol., 253, G241 (1987)]. Furthermore, abdominal surgery-induced reduced gastric function is reversed by the peptide CRF antagonist α-helical CRF (9-41) [Am. J. Physiol., 262, G616 (1992)]; and CRF promotes secretion of bicarbonate ion in the stomach, thereby lowering gastric acid secretion and suppressing cold restraint stress ulcers [Am. J. Physiol., 258, G152 (1990)]. Also, administration of CRF increases ulcers in non-restraint stress animals [Life Sci., 45, 907 (1989)], and CRF suppresses small intestinal transit and promotes large intestinal transit, and defecation is induced. In addition, the peptide CRF antagonist α-helical CRF (9-41) has a inhibiting effect against restraint stress-induced gastric acid secretion reduced gastric emptying, and small intestinal transit and accelerated large intestinal transit [Gastroenterology, 95, 1510 (1988)]; psychological stress in healthy individuals increases anxiety or sensations of gas and abdominal pain during colonic distension and CRF lowers the discomfort threshold [Gastroenterol., 109, 1772 (1995); Neurogastroenterol. Mot., 8, 9 (1996)]; irritable bowel syndrome patients experience excessive acceleration of colonic motility with CRF administration compared to healthy individuals [Gut, 42, 845 (1998)]; administration of CRF increases blood pressure, heart rate and body temperature, while the peptide CRF antagonist α-helical CRF (9-41) suppresses stress-induced increases in blood pressure, heart rate and body temperature [J. Physiol., 460, 221 (1993)]; CRF production is increased locally in inflammation sites in experimental animals and in the synovial fluid of rheumatic arthritis patients [Science, 254, 421 (1991); J. Clin. Invest., 90, 2555 (1992); J. Immunol., 151, 1587 (1993)]; CRF provokes degranulation of mast cells and promotes vascular permeability [Endocrinology, 139(1), 403 (1998); J. Pharmacol. Exp. Ther., 288(3), 1349 (1999)]; CRF is detected in autoimmune thyroiditis patients [Am. J. Pathol., 145, 1159 (1994)]; administration of CRF to experimental autoimmune encephalomyelitis rats has notably suppressed progression of symptoms such as paralysis [J. Immumol., 158, 5751 (1997)]; and urocortin (a CRF analogue) has increased growth hormone secretion in a pituitary adenoma culture system from an acromegalia patient [Endocri. J, 44, 627 (1997)]. Furthermore, CRF simulates secretion of cytokines such as interleukin-1 and interleukin-2 by leukocytes [J. Neuroimmunol., 23, 256 (1989); Neurosci. Lett., 120, 151 (1990)]; and CRF administration and stress both suppress T lymphocyte proliferation and natural killer cell activity. The peptide CRF antagonist α-helical CRF (9-41) improves the reduced function of these immune cells caused by CRF administration or stress [Endocrinology, 128(3), 1329 (1991)], and ventilation is notably increased by administration of CRF [Eur. J. Pharmacol., 182, 405 (1990)]. Finally, aggravated breathing and insomnia have been observed as a result of CRF administration to elderly patients under chronic artificial respiration [Acta Endocrinol. Copenh., 127, 200 (1992)].
The research cited above suggests that CRF antagonists may be expected to exhibit excellent effects for treatment or prevention of depression and depressive symptoms such as major depression, single-episode depression, recurrent depression, depression-induced child abuse and postpartum depression, mania, anxiety, generalized anxiety disorder, panic disorder, phobias, obsessive-compulsive disorder, posttraumatic stress disorder, Tourette's syndrome, autism, affective disorder, dysthymia, bipolar disorder, cyclothymic personality, schizophrenia, Alzheimer's disease, senile dementia of Alzheimer's type, neurodegenerative disease such as Parkinson's disease and Huntington's disease, multi-infarct dementia, senile dementia, anorexia nervosa, increased appetite and other eating disorders, obesity, diabetes, alcohol dependence, pharmacophilia for drugs such as cocaine, heroin or benzodiazepines, drug or alcohol withdrawal symptoms, sleep disorder, insomnia, migraine, stress-induced headache, muscle contraction induced headache, ischemic neuronal damage, excitotoxic neuronal damage, stroke, progressive supranuclear palsy, amyotrophic lateral sclerosis, multiple sclerosis, muscular spasm, chronic fatigue syndrome, psychosocial dwarfism, epilepsy, head trauma, spinal cord injury, cheirospasm, spasmodic torticollis, cervicobrachial syndrome, primary glaucoma, Meniere's syndrome, autonomic imbalance, alopecia, neuroses such as cardiac neurosis, gastric neurosis and bladder neurosis, peptic ulcer, irritable bowel syndrome, ulcerative colitis, Crohn's disease, diarrhea, constipation, postoperative ileus, stress-associated gastrointestinal disorders and nervous vomiting, hypertension, cardiovascular disorders such as angina pectoris nervosa, tachycardia, congestive heart failure, hyperventilation syndrome, bronchial asthma, apneusis, sudden infant death syndrome, inflammatory disorders (for example, rheumatic arthritis, osteoarthritis, lumbago, etc.), pain, allergosis (for example, atopic dermatitis, eczema, hives, psoriasis, etc.), impotence, menopausal disorder, fertilization disorder, infertility, cancer, HIV infection-related immune dysfunction, stress-induced immune dysfunction, hemorrhagic stress, Cushing's syndrome, thyroid function disorder, encephalomyelitis, acromegaly, incontinence, osteoporosis, and the like. As examples of CRF antagonists there have been reported peptide CRF receptor antagonists with modifications or deletions of portions of the amino acid sequence of human or other mammalian CRF, and such antagonists have shown ACTH release-inhibiting effects or anxiolytic effects [Science, 224, 889 (1984), J. Pharmacol. Exp. Ther., 269, 564 (1994), Brain Research Reviews, 15, 71 (1990)]. However, peptide derivatives have low utility value as drugs from the standpoint of pharmacokinetics including their chemical stability in the body, oral absorption, bioavailability and migration into the brain.
On the other hand, the following non-peptide CRF antagonists have also been reported.
[1] Compounds represented by the formula:
[wherein R1 represents NR4R5, etc.; R2 represents C1-6 alkyl, etc.; R3 represents C1-6 alkyl, etc.; R4 represents C1-6 alkyl, etc.; R5 represents C1-8 alkyl, etc.; and Ar represents phenyl, etc.], stereoisomers thereof or pharmacologically acceptable acid addition salts of the foregoing (WO97/29109);[2] Compounds represented by the formula:
[wherein the dotted lines represent single bonds or double bonds; A represents CR7, etc.; B represents NR1R2, etc.; J and K are the same or different and represent nitrogen, etc.; D and E are the same or different and represent nitrogen, etc.; G represents nitrogen, etc.; R1 represents C1-C6 alkyl, etc.; R2 represents C1-C12 alkyl, etc.; and R7 represents hydrogen, etc.] or pharmacologically acceptable salts thereof (WO98/08847);[3] The anilinopyrimidine compounds described in WO95/10506, the pyrazolopyridine compounds described in WO95/34563, the pyrazole compounds described in WO94/13661, the pyrazole compounds and pyrazolopyrimidine compounds described in WO94/13643, the aminopyrazole compounds described in WO94/13644, the pyrazolopyrimidine compounds described in WO94/13677, the pyrrolopyrimidine compounds described in WO94/13676, the thiazole compounds described in EP-659747 and EP-611766, the anilinopyrimidine compounds described in J. Med. Chem., 39, 4358 (1996), the anilinotriazine compounds described in ibid. 39, 4354 (1996) and the thienopyrimidine compounds described in WO97/29110; and[4] As pyrazolo[1,5-a]pyridine compounds, the compounds described, for example, in EP433854, EP433853 or U.S. Pat. No. 5,445,943.